Preparation of corticoids from 17-keto steroids

ABSTRACT

The present invention is a process for the transformation of a 17-keto steroid (II) to a corticoid (XI) which has pharmaceutical utility.

This is a division of application Ser. No. 264,593 filed May 18, 1981 now U.S. Pat. No. 4,357,279.

The present invention relates to a process for preparation of pharmaceutically useful corticoids for which the essential material constituting a disclosure thereof is incorporated here by reference from divisional U.S. patent application Ser. No. 264,593, filed May 18, 1981, now U.S. Pat. No. 4,357,279. 

I claim:
 1. A process for the preparation of a corticoid of the formula ##STR1## which comprises (1) contacting a protected 17-keto steroid selected from the group consisting of compounds of the formula ##STR2## with a metallated 1,2-dihalogenated ethene of the formula ##STR3## to form the corresponding protected C₂₁ -steroid selected from the group consisting of compounds of the formula ##STR4## respectively; (2) hydrolyzing the protected C₂₁ -steroid (IVa-IVe) with acid to remove the protecting group and give a C₂₁ -steroid of the formula ##STR5## (3) contacting the C₂₁ -steroid (V) with a sulfenylating agent of the formula

    R.sub.22 --S--X                                            (VI)

to give a 20,21-dihalo steroid of the formula ##STR6## (4) contacting the 20,21-dihalo steroid (VII) with a base selected from the group consisting of an alkoxide or mercaptide of the formula OR₂₀ ⁻, or SR₂₀ ⁻, respectively, to give a sulfoxide of the formula ##STR7## (5) contacting the sulfoxide (VIII) with a thiophile to give a 20-unsaturated steroid of the formula ##STR8## (6) hydrolyzing the 20-unsaturated steroid (IX) with acid to give a 21-halo steroid of the formula ##STR9## and (7) contacting the 21-halo steroid (X) with an anion of the formula R₂₁ CO.sup.⊖ where A is a fluorine, chlorine or bromine atom; M is a fluorine, chlorine or bromine atom; R₃ is alkyl of 1 thru 5 carbon atoms with the proviso that with the ketal (IIIc and IIIe), the R₃ groups can be connected to form the ethylene ketal; R₃ ' is alkyl of 1 thru 5 carbon atoms; R₃ " is alkyl of 1 thru 5 carbon atoms; R₆ is a hydrogen or fluorine atom or methyl group; R₉ is a hydrogen or fluorine atom, hydroxyl group, --OSi(R)₃ or nothing; R₁₁ is H, H,H, H, β-OH, H, β-OSi(R)₃, or O; R₁₆ is hydrogen atom or methyl group; R₂₀ is alkyl of 1 thru 4 carbon atoms or phenyl; R₂₁ is alkyl of 1 thru 4 carbon atoms or phenyl; R₂₂ is alkyl of 1 thru 5 carbon atoms, trichloromethyl, phenyl, phenyl substituted with 1-4 carbon atoms or substituted with 1 thru 3 nitro or trifluoromethyl groups, aralkyl of 7 thru 12 carbon atoms or --N--(R₁₂₂)₂ or phthalimide; X is a chlorine or bromine atom, phenylsulfone, phthalimide or imidazole group; Z is --OR₂₀ or --SR₂₀ ; metal is lithium, sodium or potassium; ∞ indicates the attached group can be in either the α or β configuration; is a single or double bond.
 2. A process according to claim 1 where for the corticoid (XI), R₆ and R₁₆ are hydrogen atoms, where R₉ is nothing and R₁₁ is [H] which gives a Δ⁹,11 functionality in the C ring.
 3. A process according to claim 1, where the temperature for the coupling reaction is from about -120° to about -20°.
 4. A process according to claim 1, where the coupling reaction is performed in a dry solvent.
 5. A process according to claim 1, where the metallated 1,2-dihalogenated ethene (III) is selected from the group consisting of lithiated trans-1,2-dichloroethene, lithiated trans-1,2-chlorofluoroethene, lithiated trans-1,2-dibromoethene, lithiated trans1,2-difluoroethene and lithiated trans-1,2-bromofluoroethene.
 6. A process according to claim 5 where the metallated 1,2-dihalogenated ethene (III) is lithiated trans-1,2-dichloroethene.
 7. A process according to claim 1, where the acid to remove the C₃ protecting group is present in a catalytic amount.
 8. A process according to claim 1, where the acid to remove the C₃ protecting group is selected from the group consisting of p-TSA, hydrochloric acid, sulfuric acid, and phosphoric acid.
 9. A process according to claim 1 where for the sulfenylating agent. R₂₂ -S-X, X is a chlorine or bromine atom, and R₂₂ is a phenyl group.
 10. A process according to claim 1 where the temperature range for the sulfenylating reaction is from about -80° to about 25°.
 11. A process according to claim 1, where the base is an alkoxide.
 12. A process according to claim 11 where the alkoxide is methoxide or phenoxide.
 13. A process according to claim 1, where the reaction with base is performed in a polar solvent.
 14. A process according to claim 1, where 1.5-2.0 equivalents of base are used.
 15. A process according to claim 1 where the thiophile is selected from the group consisting of acetone, 3-pentanone, cyclohexanone, 1-(phenylthio)acetone, 2,4-pentanedione, trimethylphosphite, mesityl oxide, dimethyl malonate, 2,6-di-t-butylphenol, ethylvinyl ether, and dihydropyran.
 16. A process according to claim 1 where the thiophile is a ketone.
 17. A process according to claim 16 where the ketone is acetone.
 18. A process according to claim 1 where the acid for hydrolyzing the 20-unsaturated steroid (IX) is p-TSA, hydrochloric acid, sulfuric acid, or phosphoric acid. 